MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus


Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H. polygyrus infection. Alongside increased parasite expulsion, MyD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4+ cells. In addition, MyD88-/- mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MyD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain-containing adapter-inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain H. polygyrus susceptibility in wild-type mice. To further investigate signaling pathways that are MyD88 dependent, we infected IL-1R1-/- mice with H. polygyrus. This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R-MyD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MyD88-deficient mice appears to be granuloma independent. Like IL-1R1-/- and MyD88-/- mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1-/-) also developed intestinal granulomas. Hence, IL-1R1, MyD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MyD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.

Publication DOI:
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Additional Information: Copyright © 2014 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
Uncontrolled Keywords: Immunology and Allergy,Immunology
Publication ISSN: 1550-6606
Last Modified: 29 Jan 2024 08:22
Date Deposited: 30 Aug 2019 13:35
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.jim ... ab-article-info (Publisher URL)
PURE Output Type: Article
Published Date: 2014-09-05
Published Online Date: 2014-09-05
Accepted Date: 2014-07-15
Authors: Reynolds, Lisa A.
Harcus, Yvonne
Smith, Katherine A.
Webb, Lauren M.
Hewitson, James P.
Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Brown, Sheila
Uematsu, Satoshi
Akira, Shizuo
Gray, David
Gray, Mohini
MacDonald, Andrew S.
Cunningham, Adam F.
Maizels, Rick M.



Version: Published Version

License: Creative Commons Attribution

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